WO1989005824A1 - Modification homogene de polypeptides specifique au site facilitant les liaisons covalentes avec une fraction hydrophile - Google Patents
Modification homogene de polypeptides specifique au site facilitant les liaisons covalentes avec une fraction hydrophile Download PDFInfo
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- WO1989005824A1 WO1989005824A1 PCT/US1988/004633 US8804633W WO8905824A1 WO 1989005824 A1 WO1989005824 A1 WO 1989005824A1 US 8804633 W US8804633 W US 8804633W WO 8905824 A1 WO8905824 A1 WO 8905824A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/53—Colony-stimulating factor [CSF]
- C07K14/535—Granulocyte CSF; Granulocyte-macrophage CSF
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5403—IL-3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5409—IL-5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/55—IL-2
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates generally to polypeptide modified by the attachment thereto of compounds having amin reactive groups, methods for producing such modified polypeptide and compositions containing the modified polypeptides. More par ticularly, the invention relates to homogeneous modified polypep tides which are modified by attachment of hydrophilic moieties including polymers, to selected positions in the polypeptide.
- a polypeptide can be modified by attachment of compound having amine reactive groups.
- treatment of a poly peptide with PEG or similar polymers can result in rando attachment of the polymer at the amino terminus of the polypep tide and/or at one or more lysine residues in the amino aci sequence of the protein.
- PEG groups can attach t the polypeptide, the end result is a composition containing o potentially containing a variety of species of "PEG-ylated polypeptide. Such heterogeneiety in composition is undesirabl for pharmaceutical use.
- the attachment of compounds with amine reactive groups to polypeptide may alter the biological activity of the polypeptid This effect is believed mediated by the position and number the attachment site(s) along the polypeptide sequence.
- site specific attachments can genera homogeneously modified polypeptides which are therapeutical efficacious and which retain certain desirable characteristics the natural polypeptides.
- This invention provides materials and methods for si specific covalent modification of polypeptides permitting t production of compositions comprising homogeneously modifi polypeptides or proteins and pharmaceutical compositio containing same.
- "Homogeneously modified” as the term is us herein means substantially consistently modified only at specif lysine residues.
- a homogeneously modified G-CSF, for exampl includes a G-CSF composition which is substantially consistent modified at position 40, but not at positions 16, 23 and 34.
- this invention first provides lysine-depleted variants ("LDVs of polypeptides of interest.
- LDVs of this invention encompa polypeptides and proteins which contain fewer reactive lysi residues than the corresponding naturally occurring or previous known polypeptides or proteins.
- the lysine residues in t peptide structure of the LDVs may occur at one or more amino ac positions occupied by lysine residues in the natural previously known counterpart, or may be located at positio occuppied by different amino acids in the parental counterpar Furthermore, LDVs may in certain cases contain more lysi residues than the parental counterpart, so long as the number lysine residues in the LDV permits homogeneous modification b reaction of the LDVs with amine-reactive moieties, as discusse below.
- polypeptides or proteins of this inventio contain a small number of lysine residues, generally six or less preferably 1 — lysines, they are also referred to herein a "LDVs" even though containing more lysine residues than th parental counterpart.
- Polypeptides of interest include both proteins and poly peptides, preferably human, useful in therapeutic, prophylacti and/ or diagnostic applications, including hematopoietins such a colony stimulating factors, e.g. G-CSF, GM-CSF, M-CSF, CSF-1, Meg-CSF,erythropoietin (EPO) , IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, B-cell growth factor, B-cell differentiation factor, eosinophi differentiation factor, erythroid potentiating activity (EPA) , macrophage activating factor, HILDA, interferons and tumo necrosis factor, among others; thrombolytic agents such as tPA, urokinase (uPA) and streptokinase and variants thereof as ar known in the art; proteins involved in coagulation an hemostasis, including Factor V, Factor VII, Factor VIII, Fact
- lysine deplete variant as the term is used herein, I ' mean variants of protein or polypeptides which are modified in amino acid structur relative to naturally occurring or previously known counterpart in one or more of the following respects:
- At least one lysine residue is inserted into the natural o previously known sequence and/or is used to replace a differen amino acid within that sequence;
- the first amino acid at the N-terminus of te matur polypeptide is preferably proline, which is a relatively non reactive amine, or is reversibly blocked with a protecting group
- one or more additional lysin residues may be inserted into the natural or previously know sequence and/or used to replace as desired other amino acid therein, e.g. arginine.
- all lysines may be deleted o replaced in accordance with (i) , and one or more new lysines ma be inserted or used to replace a different amino acid in th molecule.
- all but one or two, for example, of th lysines in the natural or previously known sequence may b deleted or replaced with other amino acids, e.g. arginine.
- the LDVs of thi invention make it possible for the first time to produce homo geneous compositions containing polypeptides or proteins (LDVs substantially specifically and consistently modified at selecte positions using amine-reactive moieties (described hereinafter as the modifying agents.
- lysine residues ar identified in those portions of the polypeptide wher modification via amino-reactive moieties is not desired. Th lysine residues so identified are deleted or replaced wit different amino acids, e.g. by genetic engineering methods a described below. Preferably replacements are conservative, i.e lysine is replaced by arginine, and where a new lysine is to b introduced, arginine by lysine. Any remaining lysine residue represent sites where modification by amine-reactive moieties i desired.
- novel lysine residue may be engineered into the polypeptide at positions wher attachment is desired, most conveniently, for example, by simpl insertion of a lysine codon into the DNA molecule at the desire site or by converting a desirably located arginine or other codo to a lysine codon.
- Convenient methods for (i) site specifi mutagenesis or DNA synthesis for producing a DNA molecul encoding the desired LDV, (ii) expression in procaryotic o eucaryotic host cells of the DNA molecule so produced, and (iii) recovery of the LDV produced by such expression are als disclosed in detail below.
- the LDVs of this invention retain useful biological properties of the natural or previously known polypeptide or protein, and may thus be used, with or without modification wit amine-reactive moieties, for applications identified for the non- modified parent polypeptide or protein. Modification with suc moieties, however, is preferred. Such modified LDVs ar producable in homogeneous compositions which, it is contemplated, will provide improved pharmacokinetic profiles and/or solubilit characteristics relative to the parent polypeptides. In cases where the parental polypeptide normally ca interact with one or more receptors, as in the case of IL-2 fo example, it is contemplated that modified LDVs of the polypeptid wherein the modification masks one or more receptor binding site may interact e.g.
- modified LDVs may represen therapeutic agents having more specific biological and pharma ⁇ o logic activities than the corresponding parental polypeptide. I cases where the parental polypeptide normally can interact wit an inhibitor, as in the case of tPA, it is contemplated tha modified LDVs of such polypeptides or proteins wherein th modification masks an inhibitor binding site may have a reduce or substantially abolished interaction with the inhibitor, an thus improved utility as a therapeutic agent.
- modified LDVs wherein the modification masks the epitop for such antibodies may represent the first potentia therapeutic, and indeed, life saving, agents.
- modified LDVs of the protein wherein th modification masks the cleavage site may represent potentia therapeutic agents with longer effective in vivo half life o other improved properties relative to the parental protein.
- Biological activity of the LDVs before or after modificatio with the amine-reactive moieties may be determined by standard i vitro or in vivo assays conventional for measuring activity .o the parent polypeptide.
- LDVs wit amine-reactive moieties are possible since such moieties wil covalently bond only to ⁇ -amino groups of the remaining lysin residue(s) in the LDVs and to the amino terminus of the LDV, i reactive.
- the modified LDVs so produced may then be recovered, and if desired, further purified and formulated with int pharmaceutical compositions by conventional methods.
- polypeptides or proteins may contain one or more lysine residues, which by virtue of peptid folding or glycosylation, for example, are not a ⁇ cesible t reaction with amine-reactive moieties, except under denaturin conditions.
- non-reactiv lysine residues may be, but need not be, altered since they wil not normally be susceptible to non-specific modification b amine-reactive moieties.
- the presence in parental polypeptides or proteins of non-reactive lysine residues may be convenientl determined, if desired, by modifying the parental polypeptide o protein with an amine-reactive compound which results in the attachment to reactive lysines of a modifying moiety of known molecular weight under denaturing and non-denaturing conditions, respectively, and determining, e.g. by SDS-PAGE analysis, the number of attached moieties in each case.
- the presence and number of additional attached moieties on the denatured parental polypeptide relative to the non-denatured parental polypeptide is a general indication of the presence and number of non-reactive lysine residues.
- any such non-reactive lysine residues may be determined, e.g. by SDS-PAGE analysis of proteolytic fragments of the polypeptide modified under denaturing and non-denaturing conditions. Lysine residues which are modified sometimes but not always under the reactio conditions selected for the practice of this invention are deeme reactive lysine residues for the purpose of this disclosure.
- Amine-reactive moieties include compounds such as succini anyhydride and polyalkylene glycols, e.g. polyethylene an polypropylene glycols, as well as derivatives thereof, with o without coupling agents or derivatization with coupling moieties, e.g. as disclosed in U.S. Patent No. 4,179,337; publishe
- the method for modifying the LDVs can be depicte as follows:
- “Lys” represents a reactive lysine residue within the polypeptid sequence
- “ ⁇ -z” represents the amine-reactive moiety
- "Y represents a hydrophilic moiety which becomes covalently linke to the ⁇ -amino group of the lysine residue (s) in the course o the depicted reaction
- "n” is an integer.
- the method comprises reacting the LDV with an amin reactive compound under suitable conditions , preferably non denaturing conditions, and in sufficient amounts permitting th covalent attachment of the hydrophilic moiety to lysin residue (s) present in the polypeptide backbone of the LDV
- suitable conditions preferably non denaturing conditions
- the amount of amine-reactive compound used should b at least equimolar to the number of lysines to be derivatized although use of excess amine-reactive compound is strongl preferred, both to improve the rate of reaction and to insur consistent modification at all reactive sites.
- the modified LD so produced may then be recovered, purified and formulated b conventional methods. See e.g., WO 87/00056 and references cite therein
- polypeptides While any polypeptide is a candidate for the method of th invention, presently desirable polypeptides to be homogeneousl modified include lymphokines and growth factors. Of significan interest are those polypeptides which affect the immune system including the colony stimulating factors, and other growt factors.
- compositions which emplo the modified polypeptide LDVs of - the present invention.
- Thes methods and compositions take advantage of the improve pharmacokinetic properties of these modified LDVs to provid treatments, e.g. , such as employing lower dosages of polypeptide less frequent administration, and more desirable distribution required for the therapeutic indications for the natura polypeptide .
- Fig. 1 is the polypeptide sequence of IL-2, with amino aci numbers used for reference in the specification.
- Fig. 2 is the polypeptide sequence of IL-3, with amino aci numbers used for reference in the specification.
- Fig. 3 is the polypeptide sequence of IL-6, with amino aci numbers used for reference in the specification.
- Fig. 4 is the polypeptide sequence of G-CSF,with amino aci numbers used for reference in the specification.
- Fig. 5 illustrates synthetic oligonucleotides for the preparatio of synthetic DNA molecules encoding exemplary IL-2 LDVs of th invention
- odd numbered oligonucleotides correspond to sequence within sense strands, even numbered oligonucleotides to anti sense strands
- the initiation ATG is marked with "***" an altered codons are underlined
- oligonucleotides in Fig. 5A yiel the LDV with alanine at position 125 and oligonucleotides in Fig. 5B yield the LDV with cystein at position 125.
- the present invention involves the selective modification o polypeptides of interest for pharmaceutical use, to both enhanc their pharmacokinetic properties and provide homogeneou compositions for human therapeutic use.
- Mos desirably, a polypeptide having one or more lysine residues i its amino acid sequence, where it would be desirable to attach a amine reactive compound, may be employed.
- polypeptide having arginine residues which may be converted to lysin residues for such attachments may be employed.
- Lysine residue may also or alternatively be inserted into, or used to replac endogenous amino acid residues, in a polypeptide a sequence whic has no conveniently located lysine or arginine residues
- lysine residues may be used to replace asparigine serine or threonine residues in consensus N-linked glycosylatio sites.
- the LDVs even when expressed i bacterial cells (and refolded if necessary or desired) , may b derivatized as disclosed herein at one or more location otherwised glycosylated when expressed in eukaryotic cells.
- the method for selectively modifying the polypeptide o choice involves selecting locations in the polypeptide sequenc for the attachment of amine reactive compounds. This step may b accomplished by altering the amino acid sequence of th polypeptide by converting selected lysine residues into arginin residues, or converting selected arginine residues into lysin residues.
- the codons AAA or AAG which code fo lysine, can be changed to the codons AGA, AGG, CGA, CGT, CGC, o CGG which code for arginine, and vice versa.
- lysine residues may be inserted into and/or deleted from peptide sequence at a selected site(s) .
- LDVs in accordance with this invention also include protein with allelic variations,i.e. sequence variations due to natura variability from individual to individual, or with other amin acid substitutions or deletions which still retain desirabl biological properties of the parental protein or polypeptide.
- All LDVs of this invention may be prepared by expressin recombinant DNA sequences encoding the desired variant in hos cells, e.g. procaryotic host cells such as E. coli. or eucaryoti host cells such as yeast or mammalian host cells, using method and materials, e.g. vectors, as are known in the art.
- DNA se quences encoding the variants may be produced synthetically or b conventional site-directed mutagenesis of DNA sequences encodin the protein or polypeptide of interest or analogs thereof.
- DNA sequences encoding various proteins of interest hav been cloned and the DNA sequences published.
- DNA sequence encoding certain proteins of interest have been deposited wit the American Type Culture Collection (See Table 1) .
- DN molecules encoding a protein of interest may be obtained (i) b cloning in accordance with published methods, (ii) from deposite plasmids, or (iii) by synthesis, e.g. using overlapping syntheti oligonucleotides based on published sequences which together spa the desired coding region.
- DNA sequences encoding individual LDV of this invention may be produced synthetically or b conventional site-directed mutagenesis of a DNA sequence encodin the parental protein or polypeptide of interest or analog thereof.
- Such methods of mutagenesis include the M13 system o Zoller and Smith, Nucleic Acids Res. i0.:6487 - 6500 (1982); Methods Enzymol. 100:468-500 (1983); and DNA 2:479-488 (1984), using single stranded DNA and the method of Morinaga et al.. Bio/technology, 636-639 (July 1984), using heteroduplexed DNA. Exemplary oligonucleotides used in accordance with such method are described below.
- each o f the LDVs o f this invention may be anal ogously produced by one skilled in the art through s i t e - dir ect ed mutagenes i s us ing approp r i at e l y chosen oligonucleotides .
- the new DNA sequences encoding the LDVs of this invention can be introduced into appropriate vectors for heterologous expression in the desired host cells , whether procaryotic or eucaryotic.
- the activity produced by the transiently transfecte or stably trans formed host cells may be measured by usin standard assays conventional for the parental protein.
- the LDV produced by expression in the genetically engineere host cells may then be purified, and if desired formulated into pharmaceutical compositions by conventional methods, ofte preferably by methods which are typically used in purifyin and/or formulating the parental protein. It is contemplated tha such pharmaceutical compositions containing the LDV in admixtur with a pharmaceutically acceptable carrier will possess simila utilities to those of the parental proteins.
- th LDVs produced by recombinant means as mentioned above are reacte with the desired amine-reactive compound under condition permitting attachment of the compound to the ⁇ -amino groups a remaining lysine residues in the peptide backbone of the LDV.
- amine reactive compound is defined herein as an compound having a reactive group capable of forming a covalen attachment to the Epsilon amine group of a lysine residue. Included among such compounds are hydrophilic polymers such a PEG and polypropylene glycol (PPG) ; compounds such as succini anhydride; and others. Methods for such attachment ar conventional, such as described in PCT application WO97/00056 an references described therein. However, by controlling the numbe and location of the remaining lysines in the LDV sequence, th number and location(s) of the attached moiety can be selectivel controlled. Such control of attachment location and numbe enables the production of only certain selectively modifie molecules retaining the desired biological activity, rather tha production of a heterogeneous mixture of variably modifie molecules, only some of which may be active.
- polypeptide LDVs of the inventio include IL-2 which has arginine residues replacing lysin residues at one or more of the lysine residues at positions 8, 9, 32, 35, 43, 48, 49, 54, 64, 76, and 97.
- IL-2 which has arginine residues replacing lysin residues at one or more of the lysine residues at positions 8, 9, 32, 35, 43, 48, 49, 54, 64, 76, and 97.
- a presently desirabl example of such a modified IL-2 has the natural lysine residu only at position 76, with all other lysine residue positions as identified above being replaced by arginine residues and wit lysine 76 being coupled to PEG.
- Amino acid numbers correlat with the numbering system used in Fig. 1 for the appropriate unmodified peptides.
- one or more of the naturally occurring lysine residues in IL-3 may be converted to a suitable amino acid, such as arginine, to create a polypeptide LDV of the invention.
- a suitable amino acid such as arginine
- one such polypeptide has positions 10, 28, 100, 110 and 116 converted to arginine and the remaining lysine residues at positions at 79 and 66 coupled to PPG.
- one or more of the arginine residues may be converted to lysine residues.
- Table 2 illustrates the positions and amino acid numbers of lysine and arginine residues in several exemplary polypeptides which can be altered according to the invention.
- position numbers correspond to the appropriate figures 1 through 4.
- EPO it may be desirable to replace all but one to about four of the endogenous lysine residues (positions 20, 45, 52, 97, 116, 140, 152 and 154) with arginine residues and/or to convert one or more of the endogenous arginine residues to lysine residues, especially at positions 4 and/or 10 and/or 162.
- IL-3 pCSF-MLA (67154) ; CSF-16 (40246) ; PHUIL3-2 (67319); pSHIL-3-1 (67326)
- WO 86/03520 Amine-reactive compounds will typically also react with th amino terminus of a polypeptide under the conditions describe above, so long as the amino terminus is accessible to amine reactive agents (i.e. reactive) and is not blocked. Therefore a alternatively modified polypeptide may be provided by blockin the reactive site on the amino terminus of the selected polypep tide LDV before reacting the LDV with the desired amine-reactiv compound. Unblocking the N-terminus after the modifying moiety, e.g.
- polymer has been covalently linked to LDV lysines wil produce a modified polypeptide with polymer or other modifyin moiety attached to the remaining lysines in the amino aci sequence of the LDV, but not at the amino terminus.
- compositions of polypeptides homogeneous for polymer attachmen or lack of polymer attachment at the amino terminus are als encompassed by this invention.
- secretory leader-encoding DNA sequence is removed from the LDV-encoding DNA, it may be desirable to additionally modify the sequence such that it encodes an N- terminus comprising Met-Pro instead of other N-termini such as Met-Ala-Pro. Such N-terminal modification permits more consistent removal of the N-terminal methionine.
- LDVs of this invention encompass LDVs containing other modifications as well, including truncation of the peptide sequence, deletion or replacement of other amino acids, insertion of new N-linked glycosylation sites, abolishment of natural N-linked glycosylation sites, etc.
- this invention encompasses LDVs encoded for by DNA molecules which are capable of hybridizing under stringent conditions to the DNA molecule encoding the parental polypeptide or protein so long as one or more lysine residues of. the parental peptide sequence is deleted or replaced with a different amino acid and/or one or more lysine residues are inserted into the parental peptide sequence and the resulting LDV is covalently modified as described herein.
- compositions for pharmaceutical use which comprise a therapeutically effective amount of a modified LDV described above in a mixture with a pharmaceutically acceptable carrier.
- a modified IL-2 may be used to treat various cancers.
- a modified G-CSF can be used to treat neutropenia, e. ° g., associated with chemotherapy.
- a modified EPO may be used for treating various anemias.
- the daily regimen should be in the range of the dosag for the natural or recombinant unmodified polypeptide, e.g. for colony stimulating factor such as G-CSF, a range of 1-10 micrograms of polypeptide per kilogram of body weight.
- the therapeutic method and compositions of the presen invention may also include co-administration with other drugs o human factors.
- the dosage recited above would be adjusted t compensate for such additional components in the therapeutic com position or regimen.
- progress of th treated patient can be monitored by periodic assessment of th hematological profile, e.g. white cell count, hematocrit and th like.
- Eukaryotic cell expression vectors into which DNA sequence encoding LDVs of this invention may be inserted may be synthesized b techniques well known to those skilled in this art.
- the compon ents of the vectors such as the bacterial replicons, selectio genes, enhancers, promoters, and the like may be obtained fro natural sources or synthesized by known procedures. See Kaufma et al., J_. Mol. Biol.. 159:601-621 (1982); Kaufman, Proc Natl. Acad. Sci. 82:689-693 (1985). See also WO 87/04187 (pMT and pMT2-ADA) and US Serial No.
- pxMT2 88,188, filed August 21 1987
- Exemplary vectors useful for mammalian expressio are also disclosed in the patent applications cited in Example 4 which are hereby incorporated by reference.
- Eucaryoti expression vectors useful in producing variants of this inventio may also contain inducible promoters or comprise inducibl expression systems as are known in the art. See US Serial No 893,115 (filed August 1, 1986) and PCT/US87/01871. -
- Established cell lines including transformed cell lines are suitable as hosts.
- - Normal diploid cells cell strain derived from .in vitro culture of primary tissue, as well a primary explants (including relatively undifferentiated cells such as haematopoeti ⁇ stem cells) are also suitable.
- Candidate cells need not be genotypically deficient in the selection gene so long as the selection gene is dominantly acting. 5
- the host cells preferably will be established mammalian cell lines.
- CHO (Chinese Hamster Ovary) cells are presently preferred.
- the vector DNA may be established mammalian cell lines.
- ⁇ 10 include all or part of the bovine papilloma virus genome (Lusky et al.. Cell. 36: 391-401 (1984) and be carried in cell lines such as C127 mouse cells as a stable episomal element.
- cell lines such as C127 mouse cells as a stable episomal element.
- Other usable mammalian cell lines include HeLa, COS-1 monkey cells, melanoma cell lines such as Bowes cells, mouse L-929 cells, 3T3
- Stable transformants then are screened for expression of the LDV' product by standard immunological or activity assays.
- the presence of the DNA encoding the LDV proteins may be detected by
- the variants so produced may be recovered, purified, and/or characterized with respect to physiochemical, biochemical and/or clinical parameters, all by known methods.
- Example 2 Bacterial and Yeast expression
- Bacterial and yeast expression may be effected by inserting (with or without synthetic linkers, as required or desired) the DNA molecule encoding the desired LDV into a suitable vector (or
- the DNA sequences encoding th LDVs are preferably modified by conventional procedures to encod only the mature polypeptide and may optionally be modified t include preferred bacterial codons.
- LDV comprises lysine residues at one or mor locations otherwise occupied in the native sequence by consensu N-linked glycosylation sites or by an O-linked glycosylatio site
- modification e.g. PEGylation
- modification e.g. PEGylation
- the bacterial (or other) expression product refolded if necessary or desired results i a polypeptide more closely mimicing the corresponding nativ glycosylated eucaryotic expression product.
- expression of the recombinant LDVs may b effected in insect cells, e.g. using the methods and material disclosed therefor in published European Applications Nos. 0 15 476 Al or 0 127 839 A2 and in Miller et al . , Geneti Engineering. Vol.8, pp.277-298 (J.K. Setlow and A. Hollander eds., Plenum Press, 1986); Pennock et al., 1984, Mol. Cell. Biol 4.: (3)399-406; or Maeda et al., 1985, Nature 315:592-594.
- Example 4 Mutagenesis Protocol Site directed mutagensis may be effected using conventiona procedures known in the art. See e.g. published Internationa
- Synthesis of such oligonucleotides may be conveniently effected using conventional automated DNA synthesis equipment and methods, typically following the manufacturer's instructions.
- oligonucleotide 6 and 7 For exam ple, to modify a DNA molecule encoding IL-2 to encode R-48, R-4 IL-2 one may mutagenize the parental DNA molecule iterativel D- using oligonucleotides 6 and 7, depicted above. Alternatively, one could mutagenize with the following oligonucleotide: G CTC ACA TTT AAG TTT TAC ATG CCC AGG AGG - GCC ACA GAA * CTG AAA CAT CTT CAG which is designed to effect both mutagenesis reactions. 5 By way of example, one may readily produce a DNA molecul and express it to yield one of the following G-CSF LDVs:
- R-23 , R-34 , R-40 G-CSF - 5 6.
- G-CSF glycosylcholine
- j represents a modification in accordance with this invention, e.g. PEGylation, at each reactive lysine residue in the LDV.
- the parental peptide sequence of G-CSF is depicted schematically at the top in brackets indicating the relative locations of positions 16, 23, 34 and 40 (occuppied by lysine residues in G-CSF) and 22, 146, 147, 166 and 169 (occupied by arginine residues in G-CSF) .
- all lysines not intended as potential attachment sites were replaced with arginine.
- lysines not intended as potential attachment sites ' may be replaced with other amino acids as well, or simply deleted, and one or more additional lysine residues may be added by insertion between or replacement of amino acid of the parental peptide sequence.
- LDV-encoding DNA may be prepared synthetically.
- a DNA molecule encoding IL-2 containing arginine residues in place of lysine residues at positions 8, 9, 32, 35, 43, 48, 54, 64 and 97 (and alanine in place of cystein at position 125) is synthesized as follows.
- the oligonucleotides depicted in Fig. 5 are synthesized by conventional means using a commercial automated DNA synthesizer following the supplier's instructions. Odd numbered oligonucleotides in Fig. 5 are "sense" strands, eve numbered oliognucleotides are "anti-sense" strands.
- Oligonucleo ⁇ tides 1 and 2, 3 and 4, 5 and 6, 7 and 8, 9 and 10, 11 and 12, 13 and 14 and 15 and 16 are annealed to each other, respectively, under conventional conditions, e.g. lOmM tris, PH 7.5, 20mM NaCl, 2mM MgCl 2/ and lOpM (combined oligonucleotides)/ ⁇ of solution, with heating to 100 C followed by slow cooling over -2 h to 37 C. The eight mixtures are then combined and the duplexes were ligated to one another under standard conditions, e.g.
- the EcoRI/Xho I cassette may then be inserted into an desired vector, e.g. pxMT2 or derivatives thereof, usin synthetic linkers as desired or necessary.
- Transformation o mammalian cells e.g. COS or CHO cells, selection o transformants, amplification of gene copy number in the case o CHO transformants, and culturing of the cells so obtained to produce the desired LDV, may be readily effected by conventional methods, such as those disclosed in the references in Table 1, above.
- the protein so produced may be recovered and furthe purified if desired, and PEGylated, and the PEGylated protein purified all by conventional methods.
- Example 8 may be repeated using the oligonucleotides depicted in Fig. 5B in place of those depicted in Fig. 5A.
- the DNA molecule so produced encodes an LDV identical to that in Example 8, except that cystein at position 125 is retained.
- the corresponding PEGylated IL-2 LDV is thus produced.
- Example 9 Preparation of PEG-ylated R-16.
- R-34, K-147 G-CSF LDV pxMT2G-CSF may be mutagenized by conventional procedures using oligonucleotides 16, 18 and 22 depicted in Example 5 to produce a pxMT2G-CSF derivative encoding the title G-CSF LDV.
- Transformation of mammalian cells, e.g. COS or CHO cells, selection of transformants, amplification of gene copy number in the case of CHO transformants, and culturing of the cells so obtained to produce the desired LDV may be readily effected by conventional methods, such as those disclosed in the references in Table 1, above.
- the protein so produced may be recovered and further purified if desired, PEGylated by conventional procedures and the PEGylated protein purified by standard methods.
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Abstract
Est décrite une protéine modifiée de manière homogène, comportant un ou plusieurs résidus de lysine sélectionnés se produisant naturellement, remplacés par un amino acide approprié, ou comportant un ou plusieurs résidus de lysine substitués en vue d'obtenir d'autres amino acides ou introduits dans une séquence polypeptidique, laissant des résidus de lysine sélectionnés comportant des groupes amino epsilon dans la protéine, et accouplant des composés réagissant aux amines à des résidus de lysine. Sont également décrits des procédés de production des protéines modifiées de manière homogène sélectionnées, ainsi que des compositions pharmaceutiques contenant de telles protéines.
Priority Applications (1)
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JP89500925A JPH02502646A (ja) | 1987-12-23 | 1988-12-22 | 親水性基に対する共有結合を容易ならしめるためのポリペプチド類の部位特異的均一修飾 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US07/137,043 US4904584A (en) | 1987-12-23 | 1987-12-23 | Site-specific homogeneous modification of polypeptides |
US137,043 | 1987-12-23 |
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WO1989005824A1 true WO1989005824A1 (fr) | 1989-06-29 |
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ID=22475573
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PCT/US1988/004633 WO1989005824A1 (fr) | 1987-12-23 | 1988-12-22 | Modification homogene de polypeptides specifique au site facilitant les liaisons covalentes avec une fraction hydrophile |
Country Status (5)
Country | Link |
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US (1) | US4904584A (fr) |
EP (1) | EP0355142A1 (fr) |
JP (1) | JPH02502646A (fr) |
AU (1) | AU2911189A (fr) |
WO (1) | WO1989005824A1 (fr) |
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GB8317880D0 (en) * | 1983-07-01 | 1983-08-03 | Searle & Co | Structure and synthesis of interferons |
GB8334102D0 (en) * | 1983-12-21 | 1984-02-01 | Searle & Co | Interferons with cysteine pattern |
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- 1988-12-22 EP EP89901043A patent/EP0355142A1/fr not_active Withdrawn
- 1988-12-22 AU AU29111/89A patent/AU2911189A/en not_active Abandoned
- 1988-12-22 WO PCT/US1988/004633 patent/WO1989005824A1/fr not_active Application Discontinuation
- 1988-12-22 JP JP89500925A patent/JPH02502646A/ja active Pending
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Also Published As
Publication number | Publication date |
---|---|
EP0355142A1 (fr) | 1990-02-28 |
AU2911189A (en) | 1989-07-19 |
JPH02502646A (ja) | 1990-08-23 |
US4904584A (en) | 1990-02-27 |
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